Inhibition of CDK-mediated Smad3 phosphorylation reduces the Pin1-Smad3 interaction and aggressiveness of triple negative breast cancer cells. Issue 15 (3rd August 2017)

• Record Type: Journal Article
• Authors: Thomas, Alexandra L.; Lind, Hanne; Hong, Angela; Dokic, Danijela; Oppat, Kailey; Rosenthal, Elana; Guo, Amina; Thomas, Aaron; Hamden, Randala; Jeruss, Jacqueline S.
• Is Part Of: Cell cycle. Volume 16:Issue 15(2017)
• Page Start: 1453
• Page End: 1464
• Publication Date: 2017-08-03
• Subjects: CDK2 -- CDK9 -- CDK inhibitor -- cyclin -- cell cycle -- EMT -- invasion -- migration -- Pin1 -- Smad3 -- TGFβ -- triple negative breast cancer; Cell cycle -- Periodicals; 571.84377
• DOI: 10.1080/15384101.2017.1338988
• Languages: English
• ISSNs: 1538-4101

Abstract

ABSTRACT: Triple negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks effective targeted therapies. Although TNBC is not defined by specific therapeutic targets, a subset of patients have tumors that overexpress cyclins. High cyclin D/E expression catalyzes CDK4/2 activity. In turn, CDK4/2 can non-canonically phosphorylate Smad3, a key TGFβ signaling intermediate, and this phosphorylation has been associated with the shift from tumor-suppressive to oncogenic TGFβ pathway action in breast oncogenesis. Additionally, CDK-mediated Smad3 phosphorylation facilitates an interaction between Smad3 and Pin1, a cis-trans isomerase that is also overexpressed in aggressive breast cancers. Treatment with CYC065, a CDK2/9 inhibitor, decreased non-canonical Smad3 phosphorylation and inhibited the Pin1-Smad3 interaction. We hypothesized that the interaction of Pin1 and Smad3, facilitated by CDK-mediated Smad3 phosphorylation, promotes TNBC cell aggressiveness. Inhibition of the Pin1-Smad3 interaction in TNBC cell lines, through depletion of Pin1 or CYC065 treatment, resulted in decreased cell migration/invasion and impeded the EMT program. Inhibition of CDK-mediated phosphorylation of Smad3 by mutagenesis also decreased cell migration, underscoring the importance of non-canonical CDK2 phosphorylation of Smad3 to enable cell motility. Pin1 depletion restored Smad3 protein levels and tumor-suppressive activity, suggesting that the Pin1-Smad3 interaction has a negative impact on canonical Smad3 action. Collectively, the data show that the Pin1-Smad3 interaction, facilitated by CDK-mediated Smad3 phosphorylation, is associated with oncogenic TGFβ signaling and breast cancer progression. Inhibition of this interaction with CYC065 treatment may provide an important therapeutic option for TNBC patients.